Can a mucosal microbiota signature predict disease severity, survival, and disease recurrence in PSC?
Authors: Phillipp Hartmann, Bernd Schnabl
Journal: Hepatology (2023)

In this issue of Hepatology, Hole et al.1 provide exciting evidence that mucosa-associated dysbiosis does not improve after liver transplantation, that it correlates with disease severity and survival, and that a specific mucosal microbiota predicts disease recurrence following transplantation in patients with primary sclerosing cholangitis (PSC). Hepatobiliary and intestinal diseases are associated with changes in the gut microbiota. Patients with PSC have characteristic alterations of the fecal microbiota with increased relative fecal abundances of Streptococcus, Veillonella, and Enterococcus, and lower proportions of Faecalibacterium prausnitzii, Coprococcus, and Lachnospiraceae.2,3 Recently, a specific PSC microbiota-associated pathobiont, Klebsiella pneumonia (K. pneumonia), has been shown to disrupt the epithelial barrier to initiate bacterial translocation and liver inflammatory responses, and to exacerbate experimental cholestatic liver disease in a microbiota-humanized mouse model.4 Further, functional aspects of microbiome changes in PSC have been investigated, where microbial plasma metabolites, including the active vitamin B6 metabolite pyridoxal 5'-phosphate and the branched-chain amino acids leucine, isoleucine, and valine, were associated with patient survival.5 Most studies have focused on luminal or fecal microbiota changes and only a minority investigated the mucosal microbiota in PSC.6 Analysis of the mucosa-adherent microbiota requires the patient to undergo an endoscopy with biopsies. However, mucosa-associated microbiota might be more relevant than luminal microbiota for disease pathogenesis, as bacterial translocation to the mesenteric lymph nodes more closely follows mucosa-associated microbiota than luminal microbiota. In addition, bacteria adherent to the mucosa might exert a more profound effect on underlying intestinal epithelial cells through microbial metabolites or other communication routes. In the current study, Hole et al.1 determined characteristic differences between mucosa-adherent microbiota of patients with PSC with/without inflammatory bowel disease (IBD), PSC patients with/without IBD following liver transplantation (PSC-LT), and healthy control subjects. Intraindividual microbial diversity was decreased in both PSC groups compared with controls. Multiple differences were noted between the groups. The relative abundance of the phylum Proteobacteria was higher in the PSC-LT group than in the PSC and control groups in multiple segments of the ileocolon, whereas Firmicutes and Desulfobacterota were decreased in various ileocolonic segments in the PSC-LT versus the control group. The proportions of the mucosa-associated genera Escherichia-Shigella were increased in PSC-LT versus PSC throughout the ileocolon, while on the contrary Pseudomonas was significantly decreased in the terminal ileum. Further, the genera Haemophilus, Veillonella, Roseburia, and genera of the Enterobacteriaceae family were more abundant in the terminal ileum, ascending, and sigmoid colon of PSC and PSC-LT groups compared with controls, whereas the genera Pseudomonas, Coprococcus, Faecalibacterium, and Romboutsia among others were scarcer. Of note, the global composition of the intestinal microbiome as determined by beta diversity, was significantly different between PSC patients with IBD and PSC patients without IBD, independent of the LT status. Moreover, they had less abundant mucosa-associated Akkermansia than PSC patients without IBD. Liver transplantation in itself causes significant microbiome changes, sometimes in a similar direction as seen with PSC, for example, the relative abundance of Enterococcus spp. increases, whereas that of Faecalibacterium (prausnitzii) decreases.7 Additionally, immunosuppressive medications commonly given to LT patients can themselves significantly alter the structure of the gut microbiome.8 A high proportion of LT patients in this study were on LT-related immunosuppressive medications, such as steroids (100% of transplanted patients), tacrolimus (84.3%), and mycophenolic acid (60.8%). The authors detected persistent PSC-specific mucosal microbiota changes independent of the LT status by identifying consistent changes between PSC versus HC groups and PSC-LT with PSC recurrence versus PSC-LT without PSC recurrence groups. LT did not reverse microbiome alterations in the current study, which is consistent with prior evidence in LT for other conditions, for example, hepatitis B,7 where LT did not normalize microbiota aberrations caused by the underlying condition. Both the PSC and PSC-LT with PSC recurrence groups had an increased relative abundance of the genera Streptococcus and Hungatella, and decreased proportions of two Lachnospiraceae genera (CAG-56 and ND3007 group) and Bilophila in at least one ileocolonic segment relative to their respective counterpart. Since similar mucosa-associated microbial changes were observed in patients with PSC and in patients with PSC recurrence following liver transplantation, the role of these five bacterial genera for disease pathogenesis should be further investigated. And indeed, following mucosa-associated microbial changes longitudinally might present a golden opportunity to study early development of recurrent disease in patients after liver transplantation. Assessment of functional changes of these mucosa-associated microbes using transcriptomic and metabolomic analyses will allow to determine if transplantation-related changes in the mucosa-associated microbiota contribute to recurrence of PSC. When examining whether this mucosal microbiota signature had predictive value for mortality, the authors found that PSC patients in the highest quartile for relative Streptococcus abundance had the shortest transplantation-free survival. Similarly, when a specific dysbiosis index is calculated using the aforementioned 5 genera (Streptococcus, Hungatella, the Lachnospiraceae genera CAG-56 and ND3007 group, and Bilophila) in the sigmoid colon, the dysbiosis index correlated positively with the Mayo PSC score, alkaline phosphatase and aspartate aminotransferase levels. The dysbiosis index was also significantly associated with LT-free survival in a multivariable Cox regression. This might hence represent a good noninvasive biomarker for disease outcome, although larger multicenter studies with biospecimen collection are required to confirm its reproducibility. Since K. pneumoniae exacerbates experimental cholestatic liver disease,4 the authors investigated its role in their cohort. Klebsiella was much more commonly detected in PSC-LT patients (41.2%) than in PSC patients (16.7%), in whom it was more common than in HCs (5%). Interestingly, PSC patients with or without LT who were positive for Klebsiella had significantly higher disease activity scores, and Klebsiella positivity was associated with significantly shorter LT-free survival. Reducing the abundance of Klebsiella specifically could be a possible therapeutic approach in PSC. K. pneumoniae hence holds promise as a target for bacteriophage therapy9 or other precision medicine approaches10 to prevent or treat this disastrous disease in the future. Of note, although this study looked at mucosa-associated microbiota in PSC, the observed alterations largely resemble fecal microbiota changes from prior PSC studies, which demonstrated that the fecal proportions of Streptococcus and Veillonella are commonly increased, and those of Faecalibacterium, Coprococcus, and Lachnospiraceae are oftentimes reduced in PSC.2,3 These results also resemble another study, where increased mucosal proportions of Streptococcus and reduced mucosal proportions of Lachnospiraceae were found in PSC patients with IBD compared with HC, although in that study the proportions of mucosa-adherent Pseudomonas were decreased.6 Within the field of hepatology, patients diagnosed with PSC and IBD are likely the only liver disease patient population that frequently undergoes colonoscopies, which allows easy access to intestinal biopsies. Outside of age-related colorectal cancer screening, colonoscopies are usually not indicated in most other liver diseases. Therefore, mucosa-associated microbiota signatures could be developed as a diagnostic tool to predict PSC onset, recurrence and outcome. More studies are indicated to firmly establish the mucosal microbiota as a biomarker. Ideally, luminal/fecal microbiota should be compared with mucosal microbiota in the same subjects over time, and correlated with translocated microbes/microbial products as well as disease severity markers in patients with PSC. Overall, this is an important study demonstrating that a specific mucosa-adherent microbial signature is associated with more severe disease in patients with PSC and with recurrent PSC after liver transplantation. Understanding the exact mechanisms by which mucosa-associated microbiota contribute to PSC, will greatly enhance our ability to design preventive and therapeutic interventions in humans. More personalized and precision medicine approaches might be required for targeted interventions against pathobionts such as K. pneumoniae. AUTHOR CONTRIBUTIONS Phillipp Hartman was responsible for writing the manuscript, Bernd Schnabl edited the manuscript. CONFLICT OF INTEREST Bernd Schnabl consults for Ambys Medicines, Ferring Research Institute and Gelesis. The remaining authors declare that they have no financial conflict of interest.